Alisertib in Combination with Weekly Paclitaxel in Patients with Advanced Breast Cancer or Recurrent Ovarian Cancer

A Randomized Clinical Trial

Gerald Falchook, Robert L. Coleman, Andrzej Roszak, Kian Behbakht, Ursula Matulonis, Isabelle Ray-Coquard, Piotr Sawrycki, Linda R. Duska, William Tew, Sharad A Ghamande, Anne Lesoin, Peter E. Schwartz, Joseph Buscema, Michel Fabbro, Alain Lortholary, Barbara Goff, Razelle Kurzrock, Lainie P. Martin, Heidi J. Gray, Siqing Fu & 6 others Emily Sheldon-Waniga, Huamao Mark Lin, Karthik Venkatakrishnan, Xiaofei Zhou, E. Jane Leonard, Russell J. Schilder

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Importance: There is an unmet medical need for the treatment of recurrent ovarian cancer, and new approaches are needed to improve progression-free survival (PFS) and overall survival. Objective: This phase 1/2 study evaluated the activity of alisertib in combination with weekly paclitaxel in patients with breast (phase 1) and ovarian cancer (phase 1 and phase 2). Design, Setting, and Participants: An open-label phase 1 and randomized phase 2 clinical trial conducted from April 16, 2010, for phase 1 and March 28, 2012, to August 12, 2013, for phase 2 was conducted at 33 sites (United States, France, and Poland). Data are reported from a cutoff date of August 12, 2014, with a median duration of follow-up of 7.2 months in the alisertib plus paclitaxel arm and 4.6 months in the paclitaxel arm. A total of 191 women with advanced breast (phase 1 only) or recurrent ovarian cancer were enrolled, including 142 patients randomized to alisertib plus paclitaxel (n = 73) or paclitaxel alone (n = 69) in the phase 2 study. Interventions: Patients were randomized 1:1 stratified by platinum-free interval (refractory, 0-6 months, 6-12 months) and prior weekly taxane treatment (yes, no) to receive alisertib 40 mg twice per day orally and 3 days on and 4 days off for 3 weeks, plus paclitaxel (60 mg/m 2 intravenously, days 1, 8, and 15), or weekly paclitaxel 80 mg/m 2 intravenously in 28-day cycles. Main Outcomes and Measures: Primary endpoint was PFS; primary efficacy analysis and safety analysis used modified intention to treat (mITT) population (all randomized patients who received ≥1 dose of study drug). Results: The median age for the 191 patients enrolled in phase 1 was 59 (range, 29-75) years. The median age for the 142 patients enrolled in phase 2 was 63 (range, 30-81) years for patients receiving alisertib plus paclitaxel and 61 (range, 41-81) years for patients receiving paclitaxel. At data cutoff, 107 (75%) patients had a documented PFS event; 52 (71%) in the alisertib plus paclitaxel arm, and 55 (80%) in the paclitaxel arm. Median PFS was 6.7 months with alisertib plus paclitaxel vs 4.7 months with paclitaxel (HR, 0.75; 80% CI, 0.58-0.96; P =.14; 2-sided P value cutoff =.20 to be considered worthy of further investigation). Drug-related grade 3 or higher adverse events were reported in 63 (86%) vs 14 (20%) patients in the alisertib plus paclitaxel and paclitaxel arms, including 56 (77%) vs 7 (10%) neutropenia, 18 (25%) vs 0 stomatitis, and 10 (14%) vs 2 (3%) anemia; 54 (74%) vs 17 (25%) had adverse events leading to dose reductions. Two patients died during the study (1 in each arm); neither death was considered related to study drug. Conclusions and Relevance: The primary endpoint, PFS, significantly favored alisertib plus paclitaxel over paclitaxel alone. Further investigation is warranted. Trial Registration: ClinicalTrials.gov identifier: NCT01091428.

Original languageEnglish (US)
JournalJAMA Oncology
Volume5
Issue number1
DOIs
StatePublished - Jan 1 2019
Externally publishedYes

Fingerprint

Paclitaxel
Ovarian Neoplasms
Randomized Controlled Trials
Breast Neoplasms
Disease-Free Survival
Arm
MLN 8237
Breast
Pharmaceutical Preparations
Stomatitis
Poland
Neutropenia
Platinum
France

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Alisertib in Combination with Weekly Paclitaxel in Patients with Advanced Breast Cancer or Recurrent Ovarian Cancer : A Randomized Clinical Trial. / Falchook, Gerald; Coleman, Robert L.; Roszak, Andrzej; Behbakht, Kian; Matulonis, Ursula; Ray-Coquard, Isabelle; Sawrycki, Piotr; Duska, Linda R.; Tew, William; Ghamande, Sharad A; Lesoin, Anne; Schwartz, Peter E.; Buscema, Joseph; Fabbro, Michel; Lortholary, Alain; Goff, Barbara; Kurzrock, Razelle; Martin, Lainie P.; Gray, Heidi J.; Fu, Siqing; Sheldon-Waniga, Emily; Lin, Huamao Mark; Venkatakrishnan, Karthik; Zhou, Xiaofei; Leonard, E. Jane; Schilder, Russell J.

In: JAMA Oncology, Vol. 5, No. 1, 01.01.2019.

Research output: Contribution to journalArticle

Falchook, G, Coleman, RL, Roszak, A, Behbakht, K, Matulonis, U, Ray-Coquard, I, Sawrycki, P, Duska, LR, Tew, W, Ghamande, SA, Lesoin, A, Schwartz, PE, Buscema, J, Fabbro, M, Lortholary, A, Goff, B, Kurzrock, R, Martin, LP, Gray, HJ, Fu, S, Sheldon-Waniga, E, Lin, HM, Venkatakrishnan, K, Zhou, X, Leonard, EJ & Schilder, RJ 2019, 'Alisertib in Combination with Weekly Paclitaxel in Patients with Advanced Breast Cancer or Recurrent Ovarian Cancer: A Randomized Clinical Trial', JAMA Oncology, vol. 5, no. 1. https://doi.org/10.1001/jamaoncol.2018.3773
Falchook, Gerald ; Coleman, Robert L. ; Roszak, Andrzej ; Behbakht, Kian ; Matulonis, Ursula ; Ray-Coquard, Isabelle ; Sawrycki, Piotr ; Duska, Linda R. ; Tew, William ; Ghamande, Sharad A ; Lesoin, Anne ; Schwartz, Peter E. ; Buscema, Joseph ; Fabbro, Michel ; Lortholary, Alain ; Goff, Barbara ; Kurzrock, Razelle ; Martin, Lainie P. ; Gray, Heidi J. ; Fu, Siqing ; Sheldon-Waniga, Emily ; Lin, Huamao Mark ; Venkatakrishnan, Karthik ; Zhou, Xiaofei ; Leonard, E. Jane ; Schilder, Russell J. / Alisertib in Combination with Weekly Paclitaxel in Patients with Advanced Breast Cancer or Recurrent Ovarian Cancer : A Randomized Clinical Trial. In: JAMA Oncology. 2019 ; Vol. 5, No. 1.
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title = "Alisertib in Combination with Weekly Paclitaxel in Patients with Advanced Breast Cancer or Recurrent Ovarian Cancer: A Randomized Clinical Trial",
abstract = "Importance: There is an unmet medical need for the treatment of recurrent ovarian cancer, and new approaches are needed to improve progression-free survival (PFS) and overall survival. Objective: This phase 1/2 study evaluated the activity of alisertib in combination with weekly paclitaxel in patients with breast (phase 1) and ovarian cancer (phase 1 and phase 2). Design, Setting, and Participants: An open-label phase 1 and randomized phase 2 clinical trial conducted from April 16, 2010, for phase 1 and March 28, 2012, to August 12, 2013, for phase 2 was conducted at 33 sites (United States, France, and Poland). Data are reported from a cutoff date of August 12, 2014, with a median duration of follow-up of 7.2 months in the alisertib plus paclitaxel arm and 4.6 months in the paclitaxel arm. A total of 191 women with advanced breast (phase 1 only) or recurrent ovarian cancer were enrolled, including 142 patients randomized to alisertib plus paclitaxel (n = 73) or paclitaxel alone (n = 69) in the phase 2 study. Interventions: Patients were randomized 1:1 stratified by platinum-free interval (refractory, 0-6 months, 6-12 months) and prior weekly taxane treatment (yes, no) to receive alisertib 40 mg twice per day orally and 3 days on and 4 days off for 3 weeks, plus paclitaxel (60 mg/m 2 intravenously, days 1, 8, and 15), or weekly paclitaxel 80 mg/m 2 intravenously in 28-day cycles. Main Outcomes and Measures: Primary endpoint was PFS; primary efficacy analysis and safety analysis used modified intention to treat (mITT) population (all randomized patients who received ≥1 dose of study drug). Results: The median age for the 191 patients enrolled in phase 1 was 59 (range, 29-75) years. The median age for the 142 patients enrolled in phase 2 was 63 (range, 30-81) years for patients receiving alisertib plus paclitaxel and 61 (range, 41-81) years for patients receiving paclitaxel. At data cutoff, 107 (75{\%}) patients had a documented PFS event; 52 (71{\%}) in the alisertib plus paclitaxel arm, and 55 (80{\%}) in the paclitaxel arm. Median PFS was 6.7 months with alisertib plus paclitaxel vs 4.7 months with paclitaxel (HR, 0.75; 80{\%} CI, 0.58-0.96; P =.14; 2-sided P value cutoff =.20 to be considered worthy of further investigation). Drug-related grade 3 or higher adverse events were reported in 63 (86{\%}) vs 14 (20{\%}) patients in the alisertib plus paclitaxel and paclitaxel arms, including 56 (77{\%}) vs 7 (10{\%}) neutropenia, 18 (25{\%}) vs 0 stomatitis, and 10 (14{\%}) vs 2 (3{\%}) anemia; 54 (74{\%}) vs 17 (25{\%}) had adverse events leading to dose reductions. Two patients died during the study (1 in each arm); neither death was considered related to study drug. Conclusions and Relevance: The primary endpoint, PFS, significantly favored alisertib plus paclitaxel over paclitaxel alone. Further investigation is warranted. Trial Registration: ClinicalTrials.gov identifier: NCT01091428.",
author = "Gerald Falchook and Coleman, {Robert L.} and Andrzej Roszak and Kian Behbakht and Ursula Matulonis and Isabelle Ray-Coquard and Piotr Sawrycki and Duska, {Linda R.} and William Tew and Ghamande, {Sharad A} and Anne Lesoin and Schwartz, {Peter E.} and Joseph Buscema and Michel Fabbro and Alain Lortholary and Barbara Goff and Razelle Kurzrock and Martin, {Lainie P.} and Gray, {Heidi J.} and Siqing Fu and Emily Sheldon-Waniga and Lin, {Huamao Mark} and Karthik Venkatakrishnan and Xiaofei Zhou and Leonard, {E. Jane} and Schilder, {Russell J.}",
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T1 - Alisertib in Combination with Weekly Paclitaxel in Patients with Advanced Breast Cancer or Recurrent Ovarian Cancer

T2 - A Randomized Clinical Trial

AU - Falchook, Gerald

AU - Coleman, Robert L.

AU - Roszak, Andrzej

AU - Behbakht, Kian

AU - Matulonis, Ursula

AU - Ray-Coquard, Isabelle

AU - Sawrycki, Piotr

AU - Duska, Linda R.

AU - Tew, William

AU - Ghamande, Sharad A

AU - Lesoin, Anne

AU - Schwartz, Peter E.

AU - Buscema, Joseph

AU - Fabbro, Michel

AU - Lortholary, Alain

AU - Goff, Barbara

AU - Kurzrock, Razelle

AU - Martin, Lainie P.

AU - Gray, Heidi J.

AU - Fu, Siqing

AU - Sheldon-Waniga, Emily

AU - Lin, Huamao Mark

AU - Venkatakrishnan, Karthik

AU - Zhou, Xiaofei

AU - Leonard, E. Jane

AU - Schilder, Russell J.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Importance: There is an unmet medical need for the treatment of recurrent ovarian cancer, and new approaches are needed to improve progression-free survival (PFS) and overall survival. Objective: This phase 1/2 study evaluated the activity of alisertib in combination with weekly paclitaxel in patients with breast (phase 1) and ovarian cancer (phase 1 and phase 2). Design, Setting, and Participants: An open-label phase 1 and randomized phase 2 clinical trial conducted from April 16, 2010, for phase 1 and March 28, 2012, to August 12, 2013, for phase 2 was conducted at 33 sites (United States, France, and Poland). Data are reported from a cutoff date of August 12, 2014, with a median duration of follow-up of 7.2 months in the alisertib plus paclitaxel arm and 4.6 months in the paclitaxel arm. A total of 191 women with advanced breast (phase 1 only) or recurrent ovarian cancer were enrolled, including 142 patients randomized to alisertib plus paclitaxel (n = 73) or paclitaxel alone (n = 69) in the phase 2 study. Interventions: Patients were randomized 1:1 stratified by platinum-free interval (refractory, 0-6 months, 6-12 months) and prior weekly taxane treatment (yes, no) to receive alisertib 40 mg twice per day orally and 3 days on and 4 days off for 3 weeks, plus paclitaxel (60 mg/m 2 intravenously, days 1, 8, and 15), or weekly paclitaxel 80 mg/m 2 intravenously in 28-day cycles. Main Outcomes and Measures: Primary endpoint was PFS; primary efficacy analysis and safety analysis used modified intention to treat (mITT) population (all randomized patients who received ≥1 dose of study drug). Results: The median age for the 191 patients enrolled in phase 1 was 59 (range, 29-75) years. The median age for the 142 patients enrolled in phase 2 was 63 (range, 30-81) years for patients receiving alisertib plus paclitaxel and 61 (range, 41-81) years for patients receiving paclitaxel. At data cutoff, 107 (75%) patients had a documented PFS event; 52 (71%) in the alisertib plus paclitaxel arm, and 55 (80%) in the paclitaxel arm. Median PFS was 6.7 months with alisertib plus paclitaxel vs 4.7 months with paclitaxel (HR, 0.75; 80% CI, 0.58-0.96; P =.14; 2-sided P value cutoff =.20 to be considered worthy of further investigation). Drug-related grade 3 or higher adverse events were reported in 63 (86%) vs 14 (20%) patients in the alisertib plus paclitaxel and paclitaxel arms, including 56 (77%) vs 7 (10%) neutropenia, 18 (25%) vs 0 stomatitis, and 10 (14%) vs 2 (3%) anemia; 54 (74%) vs 17 (25%) had adverse events leading to dose reductions. Two patients died during the study (1 in each arm); neither death was considered related to study drug. Conclusions and Relevance: The primary endpoint, PFS, significantly favored alisertib plus paclitaxel over paclitaxel alone. Further investigation is warranted. Trial Registration: ClinicalTrials.gov identifier: NCT01091428.

AB - Importance: There is an unmet medical need for the treatment of recurrent ovarian cancer, and new approaches are needed to improve progression-free survival (PFS) and overall survival. Objective: This phase 1/2 study evaluated the activity of alisertib in combination with weekly paclitaxel in patients with breast (phase 1) and ovarian cancer (phase 1 and phase 2). Design, Setting, and Participants: An open-label phase 1 and randomized phase 2 clinical trial conducted from April 16, 2010, for phase 1 and March 28, 2012, to August 12, 2013, for phase 2 was conducted at 33 sites (United States, France, and Poland). Data are reported from a cutoff date of August 12, 2014, with a median duration of follow-up of 7.2 months in the alisertib plus paclitaxel arm and 4.6 months in the paclitaxel arm. A total of 191 women with advanced breast (phase 1 only) or recurrent ovarian cancer were enrolled, including 142 patients randomized to alisertib plus paclitaxel (n = 73) or paclitaxel alone (n = 69) in the phase 2 study. Interventions: Patients were randomized 1:1 stratified by platinum-free interval (refractory, 0-6 months, 6-12 months) and prior weekly taxane treatment (yes, no) to receive alisertib 40 mg twice per day orally and 3 days on and 4 days off for 3 weeks, plus paclitaxel (60 mg/m 2 intravenously, days 1, 8, and 15), or weekly paclitaxel 80 mg/m 2 intravenously in 28-day cycles. Main Outcomes and Measures: Primary endpoint was PFS; primary efficacy analysis and safety analysis used modified intention to treat (mITT) population (all randomized patients who received ≥1 dose of study drug). Results: The median age for the 191 patients enrolled in phase 1 was 59 (range, 29-75) years. The median age for the 142 patients enrolled in phase 2 was 63 (range, 30-81) years for patients receiving alisertib plus paclitaxel and 61 (range, 41-81) years for patients receiving paclitaxel. At data cutoff, 107 (75%) patients had a documented PFS event; 52 (71%) in the alisertib plus paclitaxel arm, and 55 (80%) in the paclitaxel arm. Median PFS was 6.7 months with alisertib plus paclitaxel vs 4.7 months with paclitaxel (HR, 0.75; 80% CI, 0.58-0.96; P =.14; 2-sided P value cutoff =.20 to be considered worthy of further investigation). Drug-related grade 3 or higher adverse events were reported in 63 (86%) vs 14 (20%) patients in the alisertib plus paclitaxel and paclitaxel arms, including 56 (77%) vs 7 (10%) neutropenia, 18 (25%) vs 0 stomatitis, and 10 (14%) vs 2 (3%) anemia; 54 (74%) vs 17 (25%) had adverse events leading to dose reductions. Two patients died during the study (1 in each arm); neither death was considered related to study drug. Conclusions and Relevance: The primary endpoint, PFS, significantly favored alisertib plus paclitaxel over paclitaxel alone. Further investigation is warranted. Trial Registration: ClinicalTrials.gov identifier: NCT01091428.

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